Evolution of SARS-CoV-2 spike glycoprotein
Evolution of SARS-CoV-2 spike glycoprotein
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SARS-CoV-2 刺突糖蛋白的进化
DOI：
10.21203/rs.3.rs-29398/v1
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
S. Gamblin
中科院分区：
文献类型：
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作者：
A. Wrobel;D. Benton;P. Xu;C. Roustan;S. Martin;P. Rosenthal;J. Skehel;S. Gamblin
SARS-CoV-2的刺突糖蛋白（S）介导病毒与细胞表面受体的附着以及病毒与细胞膜之间的融合1。与SARS-CoV一样，SARS-CoV-2的受体是人类细胞表面膜蛋白ACE 22 -4。与其他1类融合糖蛋白一样，膜融合活性需要S被蛋白水解切割成S1和S2，它们在切割后保持结合4 -7。SARS-CoV-2被认为是从蝙蝠中出现的，可能是通过第二宿主8，9。为了更好地理解SARS-CoV-2的传播，我们已经通过cryoEM确定了其弗林蛋白酶切割的S的结构，这表明在这个多元氨基酸位点的切割增加了受体结合区的结构可塑性，并促进了与ACE 2受体结合所需的开放构象的采用。为了研究SARS-CoV-2和最密切相关的蝙蝠病毒RaTG 138的S蛋白之间的关系，我们已经确定并比较了它们的结构，并在生化上表征了它们对ACE 2的亲和力和它们的相对稳定性。虽然总体结构相似，但存在可能与病毒感染性相关的关键差异。这些包括更稳定的人S的预切割形式，SARS-CoV-2与人受体的结合紧密约1000倍，以及在蛋白酶切割时结合ACE 2所需的构象中S的比例更高。
The spike glycoprotein (S) of SARS-CoV-2 mediates attachment of the virus to cell surface receptors and fusion between virus and cell membranes1. The receptor for SARS-CoV-2, like that for SARS-CoV, is the human cell-surface membrane protein ACE22–4. Membrane fusion activity, as for other class-1 fusion glycoproteins, requires S to be proteolytically cleaved into S1 and S2 that remain associated following cleavage4–7. SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host8,9. To better understand the transmission of SARS-CoV-2 we have determined the structure of its furin-cleaved S by cryoEM, which shows that cleavage at this polybasic amino-acid site increases the structural plasticity of the receptor binding region and facilitates the adoption of an open conformation that is required for it to bind to the ACE2 receptor. To investigate relationships between S proteins of SARS-CoV-2 and of the most closely related bat virus, RaTG138, we have determined and compared their structures and characterised biochemically their affinities for ACE2 and their relative stabilities. Whilst the overall structures are similar, there are key differences likely pertinent to virus infectivity. These include a more stable pre-cleavage form of human S, about 1000-fold tighter binding of SARS-CoV-2 to human receptor, and a higher proportion of S in the conformation required for binding ACE2 upon protease cleavage.